Why the study?
Atogepant is an OATP substrate metabolized by CYP3A4, prompting assessment of the effects of CYP3A4 inhibition or induction and OATP inhibition on its pharmacokinetics and safety.
Does co-administration of CYP3A4 inhibitors/inducers or OATP inhibitors affect the pharmacokinetics of atogepant in healthy adults?
Does co-administration of CYP3A4 inhibitors/inducers or OATP inhibitors affect the pharmacokinetics of atogepant in healthy adults?
Atogepant systemic exposure is significantly altered by strong CYP3A4 inhibitors/inducers and OATP inhibitors, necessitating potential dose adjustments.
Atogepant exposure rises with CYP3A4/OATP modulators, warranting coadministration caution; extends Phase I DDI data for migraine therapy.
Aim: Atogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, is a substrate of OATP and metabolized by CYP3A4. Effect of multiple-dose itraconazole (strong CYP3A4 inhibitor), single-dose rifampin (strong OATP inhibitor) and multiple-dose rifampin (strong CYP3A4 inducer) on single-dose pharmacokinetics (PK) and safety of atogepant were assessed. Methods: Two phase I, open-label, single-center, crossover trials enrolled healthy adults. Results: Cmax and AUC of atogepant increased when co-administered with itraconazole. Atogepant systemic exposure increased following co-administration with single-dose rifampin. Atogepant systemic exposure decreased with co-administration of multiple-dose rifampin. Treatment emergent adverse events (TEAEs) were predominantly mild or moderate, and included constipation, dizziness, headache and nauseas. Conclusion: Systemic exposure of atogepant increased significantly when co-administered with a strong CYP3A4 or OATP inhibitor and decreased significantly when co-administered with a strong CYP3A4 inducer.
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Boinpally et al. (2023) studied this question.
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